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Predictive biomarkers for cancer therapy with PARP inhibitors

Oncogene volume 33, pages 3894–3907 (2014)Cite this article

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Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors have raised high expectations for the treatment of multiple malignancies. PARP inhibitors, which can be used as monotherapies or in combination with DNA-damaging agents, are particularly efficient against tumors with defects in DNA repair mechanisms, in particular the homologous recombination pathway, for instance due to BRCA mutations. Thus, deficient DNA repair provides a framework for the success of PARP inhibitors in medical oncology. Here, we review encouraging results obtained in recent clinical trials investigating the safety and efficacy of PARP inhibitors as anticancer agents. We discuss emerging mechanisms of regulation of homologous recombination and how inhibition of DNA repair might be used in cancer therapy. We surmise that the identification of patients that are likely to benefit from PARP inhibition will improve the clinical use of PARP inhibitors in a defined target population. Thus, we will place special emphasis on biomarker discovery.

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Abbreviations

ART:

ADP-ribosyl transferases

ATM:

ataxia-telangiectasia mutated

BER:

base excision repair

bid:

twice a day

CBR:

clinical benefit rate

CDDP:

cisplatin

CDK1:

cyclin-dependent kinase 1

DDR:

DNA damage response

DiOC6(3):

3,3′-dihexyloxacarbocyanine iodide

DLT:

dose limiting toxicity

DNA-PK:

DNA-dependent protein kinase

DNA-PKcs:

catalytic subunit of DNA-dependent protein kinase

DR:

direct repair

DSB:

double-strand break

DSBR:

double-strand break repair

EGBFr:

epidermal growth factor receptor

EOC:

epithelial ovarian cancer

GI:

gastro-intestinal

HDAC:

histone deacetylase

HzR:

hazard ratio

HR:

homologous recombination

HRD:

homologous recombination deficiency

HRR:

homologous recombinational repair

HSP90:

heat-shock protein of 90 KDa

LOH:

loss of heterozygosity

MAPK:

mitogen-activated protein kinase

MGMT:

O6-methylguanine DNA methyltransferase

MMR:

mismatch repair

MTD:

maximum tolerated dose

NAD:

nicotinamide adenine dinucleotide

NER:

nucleotide excision repair

NHEJ:

non-homologous end joining

NSCLC:

non-small-cell lung carcinoma

ORR:

overall response rate

OS:

overall survival

PAR:

poly-(ADP-ribose)

PARP:

poly-(ADP-ribose) polymerase

PARPBP:

PARP1-binding protein

PARP I:

PARP inhibitor

PLD:

pegylated liposomal doxorubicin

PD:

progressive disease

PFI:

platinum-free interval

PFS:

progression-free survival

PI:

propidium iodide

PI3K:

phosphoinositide 3-kinase

PS:

performance status

PSA:

prostate-specific antigen

PTEN:

phosphatase and tensin homolog

RECIST:

response evaluation criteria in solid tumors

RNAi:

RNA interference

SNP:

single-nucleotide polymorphism

SSB:

single-strand break

SSBR:

single-strand break repair

TMZ:

temozolomide

TNBC:

triple-negative breast cancer

XRCC1:

X-ray repair cross-complementing 1

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Acknowledgements

The authors would like to thank Lorenzo Galluzzi (Université Paris Descartes, Paris, France) for assistance with manuscript preparation. The authors are supported by the Ligue contre le Cancer (équipe labellisée), Agence National de la Recherche, AXA Chair for Longevity Research, Association pour la Recherche sur le Cancer, Associazione Italiana per la Ricerca sul Cancro (AIRC), Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale, the European Commission (ArtForce), the European Research Council, the LabEx Immuno-Oncology, Action Lions ‘Vaincre le Cancer’, Luxembourg, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (Socrate) and Cancer Research and Personalized Medicine (Carpem) and the Paris Alliance of Cancer Research Institutes.

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  1. M Castedo and G Kroemer: These authors share senior co-authorship.

Authors and Affiliations

  1. INSERM, U848, Villejuif, France

    J Michels, M Castedo & G Kroemer

  2. Institut Gustave Roussy, Villejuif, France

    J Michels, M Saparbaev, M Castedo & G Kroemer

  3. Université de Paris Sud, Villejuif, France

    J Michels, M Saparbaev, M Castedo & G Kroemer

  4. Regina Elena National Cancer Institute, Roma, Italy

    I Vitale

  5. National Institute of Health, Rome, Italy

    I Vitale

  6. CNRS UMR8200, Villejuif, France

    M Saparbaev

  7. Metabolomics Platform, Institut Gustave Roussy, Villejuif, France

    G Kroemer

  8. Centre de Recherche des Cordeliers, Paris, France

    G Kroemer

  9. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    G Kroemer

  10. Faculty of Medicine, Université Paris Descartes, Paris, France

    G Kroemer

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  1. J Michels
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  2. I Vitale
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  3. M Saparbaev
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  4. M Castedo
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  5. G Kroemer
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Corresponding authors

Correspondence to M Castedo or G Kroemer.

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Michels, J., Vitale, I., Saparbaev, M. et al. Predictive biomarkers for cancer therapy with PARP inhibitors. Oncogene 33, 3894–3907 (2014). https://doi.org/10.1038/onc.2013.352

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  • DOI: https://doi.org/10.1038/onc.2013.352

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